Mediation of in vivo analyte signal degradation

ABSTRACT

A sensor (e.g., an optical sensor) that may be implanted within a living animal (e.g., a human) and may be used to measure an analyte (e.g., glucose or oxygen) in a medium (e.g., interstitial fluid, blood, or intraperitoneal fluid) within the animal. The sensor may include a sensor housing, an analyte indicator covering at least a portion of the sensor housing, and one or more compounds having dithio-, thio- or mercapto-containing moieties that reduce degradation of the analyte indicator.

CROSS—REFERENCE TO RELATED APPLICATION

The present application claims the benefit of priority to U.S.Provisional Application Ser. No. 62/845,020, filed on May 8, 2019, whichis incorporated herein by reference in its entirety.

BACKGROUND Field of Invention

The present invention relates generally to continuous reduction of invivo degradation of analyte sensor moieties when measuring an analyte ina medium of a living animal using a system including a sensor implanted(partially or fully) or inserted into the living animal. Specifically,the present invention relates to a sensor that utilizes one or moreadditives, which may be incorporated within an analyte indicator and/ora material covering at least a portion of the analyte indicator.

Discussion of the Background

A sensor may be implanted (partially or fully) within a living animal(e.g., a human) and used to measure an analyte (e.g., glucose, oxygen,cardiac markers, low-density lipoprotein (LDL), high-density lipoprotein(HDL), or triglycerides) in a medium (e.g., interstitial fluid (ISF),blood, or intraperitoneal fluid) within the living animal. The sensormay include a light source (e.g., a light-emitting diode (LED) or otherlight emitting element), indicator molecules, and a photodetector (e.g.,a photodiode, phototransistor, photoresistor or other photosensitiveelement). Examples of implantable sensors employing indicator moleculesto measure an analyte are described in U.S. Pat. Nos. 5,517,313 and5,512,246, which are incorporated herein by reference in their entirety.

A sensor may include an analyte indicator, which may be in the form ofindicator molecules embedded in a graft (i.e., layer or matrix). Forexample, in an implantable fluorescence-based glucose sensor,fluorescent indicator molecules may reversibly bind glucose and, whenirradiated with excitation light (e.g., light having a wavelength ofapproximately 378 nm), emit an amount of light (e.g., light in the rangeof 400 to 500 nm) that depends on whether glucose is bound to theindicator molecule.

If a sensor is implanted in the body of a living animal, the animal'simmune system may begin to attack the sensor. For instance, if a sensoris implanted in a human, white blood cells may attack the sensor as aforeign body, and, in the initial immune system onslaught, neutrophilsmay be the primary white blood cells attacking the sensor. The defensemechanism of neutrophils includes the release of highly causticsubstances known as reactive oxygen species. The reactive oxygen speciesinclude, for example, hydrogen peroxide.

Hydrogen peroxide and other reactive species such as reactive oxygen andnitrogen species may degrade the indicator molecules of an analyteindicator. For instance, in indicator molecules having a boronate group,hydrogen peroxide may degrade the indicator molecules by oxidizing theboronate group, thus disabling the ability of the indicator molecule tobind glucose.

There is presently a need in the art for improvements in reducinganalyte indicator degradation. There is also a need in the art forcontinuous analyte sensors having increased longevity.

SUMMARY

The present invention overcomes the disadvantages of prior systems byproviding, among other advantages, reduced analyte indicatordegradation.

One aspect of the present invention provides a sensor that may be forimplantation or insertion within a living animal and measurement of ananalyte in a medium within the living animal. The sensor may include asensor housing, an analyte indicator covering at least a portion of thesensor housing, and one or more additives that reduce deterioration ofthe analyte indicator.

In some embodiments, the sensor may include at least oneadditive-containing polymer graft, and the one or more additives may beco-polymerized with or dispersed within the additive-containing polymergraft. In some embodiments, the additive-containing polymer graft maycover at least a portion of the sensor housing. In some embodiments, theadditive-containing polymer graft may be within the sensor housing.

In some embodiments, the one or more additives may be incorporated withthe analyte indicator, e.g., as a co-monomer. In some embodiments, thesensor may include a material, e.g., a membrane, covering at least aportion of the analyte indicator, and the one or more additives areincorporated within the material.

Further variations encompassed within the systems and methods aredescribed in the detailed description of the invention below.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and form partof the specification, illustrate various, non-limiting embodiments ofthe present invention. In the drawings, like reference numbers indicateidentical or functionally similar elements.

FIG. 1 is a schematic view illustrating a sensor system embodyingaspects of the present invention.

FIG. 2 illustrates a perspective view of a sensor embodying aspects ofthe present invention.

FIG. 3 illustrates an exploded view of a sensor embodying aspects of thepresent invention.

FIG. 4 shows percentages of glucose modulation remaining over differentdurations of implant times inside guinea pigs for samples that includeddithio-containing compounds as additives compared to controls, which didnot contain dithio-containing compounds.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

FIG. 1 is a schematic view of a sensor system embodying aspects of thepresent invention. In some non-limiting embodiment, as shown in FIG. 1,the system may include a sensor 100 and an external transceiver 101. Insome embodiments, the sensor 100 may be an implantable sensor configuredto be fully or partially implanted in a living animal (e.g., a livinghuman). The sensor 100 may be implanted, for example, in a livinganimal's arm, wrist, leg, abdomen, peritoneum, or other region of theliving animal suitable for sensor implantation. For example, in somenon-limiting embodiments, the sensor 100 may be implanted beneath theskin (i.e., in the subcutaneous or peritoneal tissues). However, this isnot required, and, in some alternative embodiments, the sensor 100 maybe a transcutaneous sensor.

In some embodiments, a transceiver 101 may be an electronic device thatcommunicates with the sensor 100 to power the sensor 100, providecommands and/or data to the sensor 100, and/or receive data from thesensor 100. In some embodiments, the received data may include one ormore sensor measurements. In some embodiments, the sensor measurementsmay include, for example and without limitation, one or more lightmeasurements from one or more photodetectors of the sensor 100 and/orone or more temperature measurements from one or more temperaturesensors of the sensor 100. In some embodiments, the transceiver 101 maycalculate analyte (e.g., glucose) concentrations from the measurementinformation received from the sensor 100.

In some non-limiting embodiments, the transceiver 101 may be a handhelddevice or an on-body/wearable device. For example, in some embodimentswhere the transceiver 101 is an on-body/wearable device, the transceiver101 may be held in place by a band (e.g., an armband or wristband)and/or adhesive, and the transceiver 101 may convey (e.g., periodically,such as every two minutes, and/or upon user initiation) measurementcommands (i.e., requests for measurement information) to the sensor 100.In some embodiments where the transceiver 101 is a handheld device,positioning (i.e., hovering or swiping/waving/passing) the transceiver101 within range over the sensor implant site (i.e., within proximity ofthe sensor 100) may cause the transceiver 101 to automatically convey ameasurement command to the sensor 100 and receive a data from the sensor100.

In some embodiments, as shown in FIG. 1, the transceiver 101 may includean inductive element 103, such as, for example, a coil. In someembodiments, the transceiver 101 may generate an electromagnetic wave orelectrodynamic field (e.g., by using a coil) to induce a current in aninductive element 114 of the sensor 100. In some non-limitingembodiments, the sensor 100 may use the current induced in the inductiveelement 114 to power the sensor 100. However, this is not required, and,in some alternative embodiments, the sensor 100 may be powered by aninternal power source (e.g., a battery).

In some embodiments, the transceiver 101 may convey data (e.g.,commands) to the sensor 100. For example, in some non-limitingembodiments, the transceiver 101 may convey data by modulating theelectromagnetic wave generated by the inductive element 103 (e.g., bymodulating the current flowing through the inductive element 103 of thetransceiver 101). In some embodiments, the sensor 100 may detect/extractthe modulation in the electromagnetic wave generated by the transceiver101. Moreover, the transceiver 101 may receive data (e.g., one or moresensor measurements) from the sensor 100. For example, in somenon-limiting embodiments, the transceiver 101 may receive data bydetecting modulations in the electromagnetic wave generated by thesensor 100, e.g., by detecting modulations in the current flowingthrough the inductive element 103 of the transceiver 101.

In some embodiments, as shown in FIG. 1, the sensor 100 may include asensor housing 102 (i.e., body, shell, capsule, or encasement), whichmay be rigid and biocompatible. In exemplary embodiments, sensor housing102 may be formed from a suitable, optically transmissive polymermaterial, such as, for example, acrylic polymers (e.g.,polymethylmethacrylate (PMMA)).

In some embodiments, as shown in FIG. 1, the sensor 100 may include ananalyte indicator 106. In some non-limiting embodiments, the analyteindicator 106 may be a polymer graft coated, diffused, adhered, orembedded on at least a portion of the exterior surface of the sensorhousing 102. The analyte indicator 106 (e.g., polymer graft) may coverthe entire surface of sensor housing 102 or only one or more portions ofthe surface of housing 102. As an alternative to coating the analyteindicator 106 on the outer surface of sensor housing 102, the analyteindicator 106 may be disposed on the outer surface of the sensor housing102 in other ways, such as by deposition or adhesion. In someembodiments, the analyte indicator 106 may be a fluorescent glucoseindicating polymer. In one non-limiting embodiment, the polymer isbiocompatible and stable, grafted onto the surface of sensor housing102, designed to allow for the direct measurement of glucose ininterstitial fluid (ISF), blood, or intraperitoneal fluid afterimplantation of the sensor 100. In some embodiments, the analyteindicator 106 may be a hydrogel.

In some embodiments, the analyte indicator 106 (e.g., polymer graft) ofthe sensor 100 may include indicator molecules 104. The indicatormolecules 104 may be distributed throughout the entire analyte indicator106 or only throughout one or more portions of the analyte indicator106. The indicator molecules 104 may be fluorescent indicator molecules(e.g., TFM having the chemical name9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracenesodium salt) or light absorbing, non-fluorescent indicator molecules. Insome embodiments, the indicator molecules 104 may reversibly bind ananalyte (e.g., glucose, oxygen, cardiac markers, low-density lipoprotein(LDL), high-density lipoprotein (HDL), or triglycerides). When anindicator molecule 104 has bound an analyte, the indicator molecule maybecome fluorescent, in which case the indicator molecule 104 is capableof absorbing (or being excited by) excitation light 329 and emittinglight 331. In one non-limiting embodiment, the excitation light 329 mayhave a wavelength of approximately 378 nm, and the emission light 331may have a wavelength in the range of 400 to 500 nm. When no analyte isbound, the indicator molecule 104 may be only weakly fluorescent.

In some embodiments, the sensor 100 may include a light source 108,which may be, for example, a light emitting diode (LED) or other lightsource that emits radiation, including radiation over a range ofwavelengths that interact with the indicator molecules 104. In otherwords, the light source 108 may emit the excitation light 329 that isabsorbed by the indicator molecules in the matrix layer/polymer 104. Asnoted above, in one non-limiting embodiment, the light source 108 mayemit excitation light 329 at a wavelength of approximately 378 nm.

In some embodiments, the sensor 100 may also include one or morephotodetectors (e.g., photodiodes, phototransistors, photoresistors orother photosensitive elements). For example, in the embodimentillustrated in FIG. 1, sensor 100 has a first photodetector 224 and asecond photodetector 226. However, this is not required, and, in somealternative embodiments, the sensor 100 may only include the firstphotodetector 224. In the case of a fluorescence-based sensor, the oneor more photodetectors may be sensitive to fluorescent light emitted bythe indicator molecules 104 such that a signal is generated by aphotodetector (e.g., photodetector 224) in response thereto that isindicative of the level of fluorescence of the indicator molecules and,thus, the amount of analyte of interest (e.g., glucose).

Some part of the excitation light 329 emitted by the light source 108may be reflected from the analyte indicator 106 back into the sensor 100as reflection light 333, and some part of the absorbed excitation lightmay be emitted as emitted (fluoresced) light 331. In one non-limitingembodiment, the emitted light 331 may have a different wavelength thanthe wavelength of the excitation light 329. The reflected light 333 andemitted (fluoresced) light 331 may be absorbed by the one or morephotodetectors (e.g., first and second photodetectors 224 and 226)within the body of the sensor 100.

Each of the one or more photodetectors may be covered by a filter 112(see FIG. 3) that allows only a certain subset of wavelengths of lightto pass through. In some embodiments, the one or more filters 112 may bethin glass filters. In some embodiments, the one or more filters 112 maybe thin film (e.g., dichroic) filters deposited on the glass and maypass only a narrow band of wavelengths and otherwise reflect most of thereceived light. In some embodiments, the filters may be thin film(dichroic) filters deposited directly onto the photo detectors and maypass only a narrow band of wavelengths and otherwise reflect most of thelight received thereby. The filters 112 may be identical (e.g., bothfilters 112 may allow signals to pass) or different (e.g., one filter112 may be a reference filter and another filter 112 may be a signalfilter).

In one non-limiting embodiment, the second (reference) photodetector 226may be covered by a reference photodiode filter that passes light at thesame wavelength as is emitted from the light source 108 (e.g., 378 nm).The first (signal) photodetector 224 may detect the amount of fluorescedlight 331 that is emitted from the molecules 104 in the analyteindicator 106. In one non-limiting embodiment, the peak emission of theindicator molecules 104 may occur around 435 nm, and the firstphotodetector 224 may be covered by a signal filter that passes light inthe range of about 400 nm to 500 nm. In some embodiments, higher glucoselevels/concentrations correspond to a greater amount of fluorescence ofthe molecules 104 in the analyte indicator 106, and, therefore, agreater number of photons striking the first photodetector 224.

In some embodiments, as shown in FIG. 1, the sensor 100 may include asubstrate 116. In some embodiments, the substrate 116 may be a circuitboard (e.g., a printed circuit board (PCB) or flexible PCB) on whichcircuit components (e.g., analog and/or digital circuit components) maybe mounted or otherwise attached. However, in some alternativeembodiments, the substrate 116 may be a semiconductor substrate havingcircuitry fabricated therein. The circuitry may include analog and/ordigital circuitry. Also, in some semiconductor substrate embodiments, inaddition to the circuitry fabricated in the semiconductor substrate,circuitry may be mounted or otherwise attached to the semiconductorsubstrate 116. In other words, in some semiconductor substrateembodiments, a portion or all of the circuitry, which may includediscrete circuit elements, an integrated circuit (e.g., an applicationspecific integrated circuit (ASIC)) and/or other electronic components,may be fabricated in the semiconductor substrate 116 with the remainderof the circuitry is secured to the semiconductor substrate 116, whichmay provide communication paths between the various secured components.

In some embodiments, the one or more of the sensor housing 102, analyteindicator 106, indicator molecules 104, light source 108, photodetectors224, 226, temperature transducer 670, substrate 116, and inductiveelement 114 of sensor 100 may include some or all of the featuresdescribed in one or more of U.S. application Ser. No. 13/761,839, filedon Feb. 7, 2013, U.S. application Ser. No. 13/937,871, filed on Jul. 9,2013, U.S. application Ser. No. 13/650,016, filed on Oct. 11, 2012, U.S.9,681,824 (Colvin and Jiang), and U.S. Pat. No. 9,427,181 (Emken etal.), all of which are incorporated by reference in their entireties.Similarly, the structure and/or function of the sensor 100 and/ortransceiver 101 may be as described in one or more of U.S. applicationSer. Nos. 13/761,839, 13/937,871, and 13/650,016.

In some embodiments, the sensor 100 may include a transceiver interfacedevice, and the transceiver 101 may include a sensor interface device.In some embodiments where the sensor 100 and transceiver 101 include anantenna or antennas (e.g., inductive elements 103 and 114), thetransceiver interface device may include the inductive element 114 ofthe sensor 100, and the sensor interface device may include theinductive element 103 of the transceiver 101. In some of thetranscutaneous embodiments where there exists a wired connection betweenthe sensor 100 and the transceiver 101, the transceiver interface deviceand sensor interface device may include the wired connection.

FIGS. 2 and 3 illustrate a non-limiting embodiment of a sensor 100embodying aspects of the present invention that may be used in thesensor system illustrated in FIG. 1. FIGS. 2 and 3 illustrateperspective and exploded views, respectively, of the non-limitingembodiment of the sensor 100.

In some embodiments, as illustrated in FIG. 3, the sensor housing 102may include an end cap 113. In some embodiments, the sensor 100 mayinclude one or more capacitors 118. The one or more capacitors 118 maybe, for example, one or more tuning capacitors and/or one or moreregulation capacitors. The one or more capacitors 118 may be too largefor fabrication in the semiconductor substrate 116 to be practical.Further, the one or more capacitors 118 may be in addition to one ormore capacitors fabricated in the semiconductor substrate 116.

In some embodiments, as illustrated in FIG. 3, the sensor 100 mayinclude a reflector 119 (i.e., mirror). Reflector 119 may be attached tothe semiconductor substrate 116 at an end thereof. In a non-limitingembodiment, reflector 119 may be attached to the semiconductor substrate116 so that a face portion 121 of reflector 119 is generallyperpendicular to a top side of the semiconductor substrate 116 (i.e.,the side of semiconductor substrate 116 on or in which the light source108 and one or more photodetectors 110 are mounted or fabricated) andfaces the light source 108. The face 121 of the reflector 119 mayreflect radiation emitted by light source 108. In other words, thereflector 119 may block radiation emitted by light source 108 fromexiting the axial end of the sensor 100.

According to one aspect of the invention, an application for which thesensor 100 was developed (although by no means the only application forwhich it is suitable) is measuring various biological analytes in theliving body of an animal (including a human). For example, sensor 100may be used to measure glucose, oxygen, toxins, pharmaceuticals or otherdrugs, hormones, and other metabolic analytes in, for example, the humanbody.

In some embodiments, the specific composition of the analyte indicator106 and the indicator molecules 104 may vary depending on the particularanalyte the sensor is to be used to detect and/or where the sensor is tobe used to detect the analyte (e.g., in the in subcutaneous tissues,blood, or peritoneum). In some embodiments, the analyte indicator 106facilitates exposure of the indicator molecules 104 to the analyte. Insome embodiments, the indicator molecules 104 may exhibit acharacteristic (e.g., emit an amount of fluorescence light) that is afunction of the concentration of the specific analyte to which theindicator molecules 104 are exposed.

In some embodiments, the sensor 100 may include at least one drugeluting polymer matrix and/or a layer of catalyst and/or one or moretherapeutic agents that may be provided on, incorporated in, ordispersed within the analyte indicator or sensor housing as described inU.S. Pat. No. 9,931,068 (Huffstetler et al.), which is incorporatedherein by reference in its entirety. In some embodiments, the one ormore therapeutic agents may be incorporated in the analyte indicator106. In some embodiments, the sensor 100 may include a membrane coveringat least a portion of the analyte indicator 106, and the one or moretherapeutic agents may be incorporated within the membrane. In someembodiments, the one or more therapeutic agents include dexamethasone,triamcinolone, betamethasone, methylprednisolone, beclometasone,fludrocortisone, derivatives thereof, and analogs thereof, aglucocorticoid, an anti-inflammatory drug, e.g., a non-steroidalanti-inflammatory drug including but not limited to acetylsalicylicacid, isobutylphenylpropanoic acid.

The implantation or insertion of a medical device, such as a bio-sensor,into a user/patient's body can cause the body to exhibit adversephysiological reactions that are detrimental to the functioning of thedevice. The reactions may range from infections due to implantationsurgery to the immunological response of a foreign object implanted inthe body. That is, the performance of the implantable bio-sensor can behindered or permanently damaged in vivo via the immunological responseto an infection or the device itself. In particular, the performance ofthe analyte indicator 106 may be deteriorated by the immunologicalresponse of the body into which the sensor 100 is implanted. Forexample, as explained above, white blood cells, including neutrophils,may attack an implanted sensor 100. The neutrophils release, inter alia,hydrogen peroxide, which may degrade indicator molecules 104 (e.g., byoxidizing a boronate group of an indicator molecule 104 and disablingthe ability of the indicator molecule 104 to bind glucose).

In some embodiments, the analyte indicator 106 may include one or moreadditives that interact or react with one or more degradative specieswithout compromising signal integrity or performance of the sensordevice. The degradative species may include one or more of hydrogenperoxide, a reactive oxygen species, a reactive nitrogen species, a freeradical, an enzyme, and a metal ion. In some embodiments, the additivemay be incorporated into the analyte indicator 106 that may cover atleast a portion of the sensor housing 102. In some embodiments, theadditive may be copolymerized with the indicator molecules 104. In someembodiments, the one or more additives may be provided in the analyteindicator 106 (e.g., polymer graft). In some embodiments, the one ormore additives may interact and/or react with degradative species. Insome embodiments, the one or more additives may neutralize thedegradative species. In some embodiments, the one or more additives maybind to the degradative species. In some embodiments, the one or moreadditives may sequester the degradative species so as to inhibit,reduce, and/or prevent degradation of the analyte indicator by thedegradative species. Accordingly, in some embodiments, the one or moreadditives reduce deterioration of the analyte indicator 106.

In some non-limiting embodiments, the one or more additives may bedithio-, thio-, or mercapto-containing moieties that interact withdegradative species without compromising signal integrity or performanceof the sensor.

In some non-limiting embodiments, a sensor 100 for measurement of ananalyte (e.g., glucose) in a medium (e.g., interstitial fluid) within aliving animal (e.g., a human) contains one or more of the followingcomponents: a sensor housing 102; a light source 108 within the sensorhousing 102 configured to emit excitation light 329; an analyteindicator 106 covering a portion of the sensor housing 102; one or moreindicator molecules 104 that are part of (e.g. distributed throughout)the analyte indicator 106, reversibly bind the analyte, are positionedto be irradiated by the excitation light 329, and are configured to emitlight 331 indicative of the amount of the analyte in the medium withinthe living animal; one or more photodetectors 224 within the sensorhousing 102 that are sensitive to light 331 emitted by the one or moreindicator molecules 104 and configured to generate a signal indicativeof the amount of the analyte in the medium within the living animal; oneor more photodetectors 226 within the sensor housing 102 that aresensitive to reflection light 333 and configured to generate a referencesignal indicative of the amount of received reflection light 333; andone or more compounds having dithio-, thio- or mercapto-containingmoieties that interact with degradative species without compromisingsignal integrity or performance of the sensor 100. In some non-limitingembodiments, the sensor 100 may include a drug eluting matrix and/or alayer of catalyst provided on or incorporated in the analyte indicator106.

In some non-limiting embodiments, one or more of the compounds havingdithio-, thio- or mercapto-containing moieties may be:

a dithio compound of Formula I: R1-S—S—R2,

a thio compound of Formula II: R1-S—R2,

a mercapto compound of formula III: R3-SH,

wherein R1, R2, and R3 are each independently selected from an alkyl, anaryl, a substituted alkyl, a substituted phenyl, a substituted aryl, ora combination thereof. In some aspects, the substitute alkyl,substituted phenyl, or substituted aryl may be substituted with anyappropriate molecule including, e.g., one or more halogens orhalogen-containing molecules, one or more hydroxyl groups, one or moreacyl groups, one or more acyloxy groups, one or more alkoxy groups, oneor more aryl groups, one or more carboxy groups, one or more carbonylgroups, one or more alkylcarboxy groups, one or more alkylsufonoxygroups, one or more alkylcarbonyl groups, one or more nitro groups, oneor more cyano groups, one or more acylamido groups, one or more phenylgroups, one or more tolyl groups, one or more chlorophenyl groups, oneor more alkoxyphenyl groups, one or more halophenyl groups, one or morebenzoxazole groups, one or more thiazoline groups, one or morebenzimidazole groups, one or more oxazole groups, one or more thiazolegroups, one or more indole groups, etc., or a combination thereof. Insome aspects, the alkyl or substituted alkyl may be a C1 to C30 alkyl.In some aspects, the alkyl may be branched or unbranched. In someaspects, the aryl may be heterocyclic, polycyclic, or monocyclic.

In some aspects, one or more compounds having dithio-, thio- ormercapto-containing moieties may be selected from:3,3′-Dithiodipropionic acid; 3,3′-Dithiodipropionic aciddi(N-hydroxysuccinimide ester); 4,4′-Dithiodibutyric acid;Dithiodiglycolic acid; 2-Hydroxyethyl disulfide; S,S′-Methylenebis(3-Mercaptopropionic acid); Dimethyl 3,3′-dithiopropionimidatedihydrochloride; 3-Mercaptopropionic acid; 6,6′-Dithiodinicotinic acid;Dimethyl 3,3′-dithiopropionimidate dihydrochloride; Lipoic acid;1,2-Dithiolane-3-pentanoic acid; Lipoic acid, reduced; Thioctic acid;ditridecyl thiodipropionate; distearyl thiodipropionate; dimyristylthiodipropionate; Dilauryl thiodipropionate; 3,3′-Thiodipropionic acid;3,3′-Thiodipropionic acid; Didodecyl 3,3′-thiodipropionate;2,2′-Thiodiacetic acid; 4,4′-Thiodiphenol; Thiodipropionic acid dilaurylester; 3,3′-Thiodipropanol; Glutathione; 2,2′-(Ethylenedithio)diaceticacid; Ergothioneine; Methionine; 3-Mercaptopropane-1,2-dio; dithionatesalts including but not limited to sodium salts thereof; thioglycolatesalts including but not limited to sodium salts thereof; thiomalatesalts including but not limited to sodium salts thereof; andLipoyllysine.

In some aspects, one or more compounds having dithio-, thio- ormercapto-containing moieties may be selected from cysteine andderivatives thereof including but not limited to N-Acetyl Cysteine,cysteic acid, homocysteic acid, cysteine sulfinic acid, and compoundsrepresented by Formula IV:

[Formula IV], or a salt, ester, hydrate, solvate, or amide thereof.Examples of suitable base salts, hydrates, esters, or solvates includehydroxides, carbonates, and bicarbonates of ammonia, alkali metal saltssuch as sodium, lithium and potassium salts, alkaline earth metal saltssuch as calcium and magnesium salts, aluminum salts, and zinc salts.Organic bases suitable for the formation of pharmaceutically acceptablebase addition salts, hydrates, esters, or solvates of the compounds ofthe present invention include those that are non-toxic and strong enoughto form such salts, hydrates, esters, or solvates. For purposes ofillustration, the class of such organic bases may include mono-, di-,and trialkylamines, such as methylamine, dimethylamine, triethylamineand dicyclohexylamine; mono-, di- or trihydroxyalkylamines, such asmono-, di-, and triethanolamine; amino acids, such as arginine andlysine; guanidine; N-methyl-glucosamine; N-methyl-glucamine;L-glutamine; N-methyl-piperazine; morpholine; ethylenediamine;N-benzyl-phenethylamine; (trihydroxy-methyl)aminoethane; and the like.See, for example, “Pharmaceutical Salts,” J. Pharm. Sci., 66:1, 1-19(1977). Accordingly, basic nitrogen-containing groups can be quaternizedwith agents including: lower alkyl halides such as methyl, ethyl,propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates suchas dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halidessuch as decyl, lauryl, myristyl and stearyl chlorides, bromides andiodides; and aralkyl halides such as benzyl and phenethyl bromides.

The salts, hydrates, esters, or solvates of the basic compounds may beprepared either by dissolving the free base of a oxathiazin-likecompound in an aqueous or an, aqueous alcohol solution or other suitablesolvent containing the appropriate acid or base, and isolating the saltby evaporating the solution. Alternatively, the free base of theoxathiazin-like compound may be reacted with an acid, as well asreacting the oxathiazin-like compound having an acid group thereon witha base, such that the reactions are in an organic solvent, in which casethe salt separates directly or can be obtained by concentrating thesolution.

In some non-limiting embodiments, the one or more compounds havingdithio-, thio- or mercapto-containing moieties may be provided in theanalyte indicator 106 (e.g., polymer graft or hydrogel) of the analytesensor 100. In some non-limiting aspects, the one or more compoundshaving dithio-, thio- or mercapto-containing moieties are entrapped in ahydrogel covering at least a portion of the sensor housing, and thehydrogel entrapping the one or more compounds having dithio-, thio- ormercapto-containing moieties is separate and distinct from the analyteindicator. In some non-limiting embodiments, one or more compoundshaving dithio-, thio- or mercapto-containing moieties may beincorporated into the analyte indicator 106 by a method including one ormore of the followings steps: (i) providing the analyte indicator 106 onthe outer surface of the sensor housing 102, (ii) preparing acomposition including the one or more compounds having dithio-, thio- ormercapto-containing moieties (e.g., preparing a solution of the one ormore compounds having dithio-, thio- or mercapto-containing moieties ina solvent), (iii) inserting the analyte sensor 100 into the compositionfor an amount of time sufficient to effect soaking of the compositioninto the analyte indicator 106 on the sensor housing 102, (iv) removingthe analyte sensor 100 from the composition, and (v) drying the analytesensor 100. In some aspects, the solvent may include, for example andwithout limitation, an alcohol (e.g., isopropanol, ethanol, ormethanol), water, or a combination thereof. In some aspects, thecomposition may include, for example and without limitation, about 0.01to about 25% by weight of the compounds having one or more compoundshaving dithio-, thio- or mercapto-containing moieties (e.g., 0.01, 0.05,0.1, 0.5, 1, 2, 5, 10, 15, 20, 25% by weight, or any integer or fractionthereof falling in the range between 0.01 and 25% by weight of thecomposition of the compounds having one or more compounds havingdithio-, thio- or mercapto-containing moieties). In some aspects, theanalyte sensor 100 may remain in the composition for amount of time in arange from about 5 minutes to about 24 hours (e.g., 5, 10, 20, 30, 40,50, or 60 minutes, or 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24hours, or any specific time period falling in the range between 5minutes and 24 hours). In some aspects, the analyte sensor 100 may beair dried.

In some aspects, the one or more compounds having dithio-, thio- ormercapto-containing moieties may be polymerized as a co-monomer with anindicator monomer and one or more acrylate monomers. In somenon-limiting embodiments, one or more compounds having dithio-, thio- ormercapto-containing moieties may be provided as co-monomers of fourmonomers according to Formula V:

ABCD   [Formula V],

wherein A is an indicator monomer, B is a methacrylate monomer, C is apolyethylene glycol monomer, and D is a dithio-, thio- ormercapto-containing moiety monomer, wherein A is 0 to 10% by weight, Bis 1 to 99% by weight, C is 1 to 99% by weight, and D is 1 to 99% byweight of the total polymer.

In some non-limiting embodiments, the analyte indicator 106 may contain:(i) the TFM fluorescent indicator, (ii) hydroxyethylmethacrylate (HEMA),which is a methacrylate, (iii) polyethylene glycol (PEG), and (iv) oneor more compounds having dithio-, thio- or mercapto-containing moieties.In some embodiments, the PEG may be polyethylene glycol methacrylate(PEG-methacrylate) or polyethylene glycol diacrylate (PEG-diacrylate orPEGDA). In some embodiments, i) through iv) may be provided in specificweight ratios. For example, in some non-limiting embodiments in whichthe analyte indicator 106 is opaque, the analyte indicator 106 maycomprise 0.001 to 10% by weight, HEMA may comprise 1 to 99% by weight,PEGDA may comprise 1 to 99% by weight of the total polymer, and the oneor more compounds having dithio-, thio- or mercapto-containing moietiesmay comprise 0.01 to 200% by weight of the total polymer.

In some embodiments, the relative molar percent of the one or morecompounds having dithio-, thio- or mercapto-containing moieties may bewithin a specific range. In some embodiments, the relative mass percentof the one or more compounds having dithio-, thio- ormercapto-containing moieties ranges between 0.01 and 200 percent of thetotal polymer.

In some embodiments, the PEGDA may act as a cross-linker and create asponge-like matrix/hydrogel. In some non-limiting embodiments, thePEG-containing graft/hydrogel may become clear if a sufficient amount ofadditional PEG is added to the mixture (i.e., if it is fabricated with ahigher concentration of PEG), and a clear polymer graft 106 may be madefrom such a formulation. In some embodiments, the polymer graft may besynthesized using conventional free radical polymerization.

In some embodiments, an implanted sensor including anadditive-containing analyte indicator may have improved performance overa sensor that does not include an additive-containing analyte indicator.For instance, in some non-limiting embodiments, the additive may improvethe longevity and/or functionality of the sensor 100.

FIG. 4 shows experimental results of sensor longevity comparing sensorshaving no dithio-, thio- or mercapto-containing moieties (Control) withnon-limiting embodiments of sensors 100 having one or more compoundshaving dithio-, thio- or mercapto-containing moieties in the analyteindicator 106 implanted subcutaneously in guinea pigs for up to 90 days.

Device samples were produced by first making the controls where theindicator hydrogels did not contain dithio or other additives. Theinvestigational devices were produced by taking some of the controldevices, and thereafter soaking for one hour at ambient temperatureinside 5% (by weight) solutions of 3,3-dithiodipropionic acid (DTDP) inethanol, followed by air-drying for 16 hours. Controls andinvestigational devices were implanted in the subcutaneous regions ofguinea pigs. Necropsies were conducted after different points of time(0, 30, 48, 65, and 90 days), and the fluorescence signals of theexplanted devices were measured using fluorometers. Fluorescence signalswere measured at 0 mM and 18 mM glucose concentrations, and % Glucosemodulations were calculated as follows: % Glucose Modulation=[1−(Signalat 18 mM glucose)/(Signal at 0 mM glucose)]×100. % Glucose modulationsat different points of times were normalized with respect to Day 0, orin other words un-implanted devices.

FIG. 4 shows that the % modulations of control as well asinvestigational devices diminished with increasing durations of beingimplanted. However, at all time-points, the investigational devices(DTDP) were consistently greater than the controls. For example, onDay=65 the Investigational device containing DTDP was modulating at 63%of its original Day 0 signal, whereas the Control was modulating atsignificantly lower modulation of 28%. This shows that that DTDPadditives helped retain significantly greater glucose modulation powerin the indicator hydrogel.

Embodiments of the present invention have been fully described abovewith reference to the drawing figures. Although the invention has beendescribed based upon these preferred embodiments, it would be apparentto those of skill in the art that certain modifications, variations, andalternative constructions could be made to the described embodimentswithin the spirit and scope of the invention. For example, although insome embodiments, the analyte sensor 100 may be an optical sensor, thisis not required, and, in one or more alternative embodiments, theanalyte sensor may be a different type of analyte sensor, such as, forexample, an electrochemical sensor, a diffusion sensor, or a pressuresensor. Also, although in some embodiments, the analyte sensor 100 maybe an implantable sensor, this is not required, and, in some alternativeembodiments, the analyte sensor may be a transcutaneous sensor having awired connection to an external transceiver. For example, in somealternative embodiments, the analyte sensor 100 may be located in or ona transcutaneous needle (e.g., at the tip thereof). In theseembodiments, instead of wirelessly communication using an antenna (e.g.,inductive element 114), the analyte sensor may communicate with theexternal transceiver using one or more wires connected between theexternal transceiver and a transceiver transcutaneous needle includingthe analyte sensor. For another example, in some alternativeembodiments, the analyte sensor may be located in a catheter (e.g., forintravenous blood glucose monitoring) and may communicate (wirelessly orusing wires) with an external transceiver.

What is claimed is:
 1. A sensor for measurement of an analyte in a medium within a living animal, the sensor comprising: a sensor housing; an analyte indicator covering at least a portion of the sensor housing; and one or more compounds having dithio-, thio- or mercapto-containing moieties.
 2. The sensor of claim 1, wherein the sensor is implantable within a living animal.
 3. The sensor of claim 1, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are incorporated into the analyte indicator.
 4. The sensor of claim 1, wherein the analyte indicator is a hydrogel.
 5. The sensor of claim 1, wherein one or more compounds having dithio-, thio- or mercapto-containing moieties are entrapped in a hydrogel covering at least a portion of the sensor housing, and the hydrogel entrapping the one or more compounds having dithio-, thio- or mercapto-containing moieties is separate and distinct from the analyte indicator.
 6. The sensor of claim 1, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties interact or react with a degradative species without compromising signal integrity or performance of the sensor device, wherein the degradative species is hydrogen peroxide, a reactive oxygen species, a reactive nitrogen species, a free radical, an enzyme, or a metal ion.
 7. The sensor of claim 1, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties reduce a degradation rate of the analyte indicator.
 8. The sensor of claim 6, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties bind to the degradative species.
 9. The sensor of claim 6, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties sequester the degradative species so as to reduce, and/or prevent degradation of the analyte indicator by the degradative species.
 10. The sensor of claim 1, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are selected from: a) a dithio compound of Formula I: R1-S—S—R2, b) a thio compound of Formula II: R1-S—R2, c) a mercapto compound of formula III: R3-SH, wherein each of R1, R2, and R3 is independently an alkyl, an aryl, a substituted alkyl, a substituted phenyl, a substituted aryl, or a combination thereof.
 11. The sensor of claim 1, wherein the one or more compounds having dithio-, thio-, or mercapto-containing moieties are selected from: 3,3′-Dithiodipropionic acid; 3,3′-Dithiodipropionic acid di(N-hydroxysuccinimide ester); 4,4′-Dithiodibutyric acid; Dithiodiglycolic acid; 2-Hydroxyethyl disulfide; S,S′-Methylenebis (3-Mercaptopropionic acid); Dimethyl 3,3′-dithiopropionimidate dihydrochloride; 3-Mercaptopropionic acid; 6,6′-Dithiodinicotinic acid; Dimethyl 3,3′-dithiopropionimidate dihydrochloride; Lipoic acid; 1,2-Dithiolane-3-pentanoic acid; Lipoic acid, reduced; Thioctic acid; ditridecyl thiodipropionate; distearyl thiodipropionate; dimyristyl thiodipropionate; Dilauryl thiodipropionate; 3,3′-Thiodipropionic acid; 3,3′-Thiodipropionic acid; Didodecyl 3,3′-thiodipropionate; 2,2′-Thiodiacetic acid; 4,4′-Thiodiphenol; Thiodipropionic acid dilauryl ester; 3,3′-Thiodipropanol; Glutathione; 2,2′-(Ethylenedithio)diacetic acid; Ergothioneine; Methionine; 3-Mercaptopropane-1,2-dio; dithionate salts; thioglycolate salts; thiomalate salts; and Lipoyllysine.
 12. The sensor of claim 1, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are selected from: cysteine and compounds represented by Formula IV:

or a salt, ester, hydrate, solvate, or amide thereof.
 13. The sensor of claim 1, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are selected from N-Acetyl Cysteine, cysteic acid, homocysteic acid, cysteine sulfinic acid, or a salt, ester, hydrate, solvate, or amide thereof.
 14. The sensor of claim 1, wherein the sensor comprises at least one drug eluting polymer matrix that covers at least a portion of the sensor housing.
 15. A method of fabricating a sensor for measurement of an analyte in a medium within a living animal, the method comprising: inserting the sensor into a composition for an amount of time sufficient to effect soaking of the composition into the analyte indicator, wherein the sensor includes a sensor housing and an analyte indicator that covers at least a portion of the sensor housing, and the composition comprises one or more compounds having dithio-, thio- or mercapto-containing moieties; and removing the sensor from the composition.
 16. The method of claim 15, further comprising applying an analyte indicator to a sensor housing of the sensor such that the applied analyte indicator covers at least a portion of the sensor housing before the inserting step.
 17. The method of claim 15, further comprising preparing the composition comprising the one or more compounds having dithio-, thio- or mercapto-containing moieties before the inserting step.
 18. The method of claim 15, wherein the amount of time is sufficient to effect soaking of the composition into the analyte indicator.
 19. The method of claim 15, wherein the composition comprises the one or more compounds having dithio-, thio- or mercapto-containing moieties and a solvent.
 20. The method of claim 19, wherein the solvent comprises an alcohol, water, or a combination thereof.
 21. The method of claim 15, wherein the composition comprises about 0.01 to about 25% by weight of the compounds having one or more compounds having dithio-, thio- or mercapto-containing moieties.
 22. The method of claim 15, wherein the amount of time is between about 5 minutes and about 24 hours.
 23. The method of claim 15, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are entrapped in a hydrogel covering at least a portion of the sensor housing, and the hydrogel entrapping the one or more compounds having dithio-, thio- or mercapto-containing moieties is separate and distinct from the analyte indicator.
 24. The method of claim 15, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties reduce oxidation of the analyte indicator.
 25. The method of claim 15, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties interact or react with a degradative species without compromising signal integrity or performance of the sensor device, wherein the degradative species is hydrogen peroxide, a reactive oxygen species, a reactive nitrogen species, an enzyme, a free radical, or a metal ion.
 26. The method of claim 25, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties sequester the degradative species so as to reduce and/or prevent degradation of the analyte indicator by the degradative species.
 27. The method of claim 15, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are selected from: a) a dithio compound of Formula I: R1-S—S—R2, b) a thio compound of Formula II: R1-S—R2, c) a mercapto compound of formula III: R3-SH wherein each of R1, R2, and R3 is independently an alkyl, an aryl, a substituted alkyl, a substituted phenyl, a substituted aryl, or a combination thereof.
 28. The method of claim 15, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are selected from: 3,3′-Dithiodipropionic acid; 3,3′-Dithiodipropionic acid di(N-hydroxysuccinimide ester); 4,4′-Dithiodibutyric acid; Dithiodiglycolic acid; 2-Hydroxyethyl disulfide; S,S′-Methylenebis (3-Mercaptopropionic acid); Dimethyl 3,3′-dithiopropionimidate dihydrochloride; 3-Mercaptopropionic acid; 6,6′-Dithiodinicotinic acid; Dimethyl 3,3′-dithiopropionimidate dihydrochloride; Lipoic acid; 1,2-Dithiolane-3-pentanoic acid; Lipoic acid, reduced; Thioctic acid; ditridecyl thiodipropionate; distearyl thiodipropionate; dimyristyl thiodipropionate; Dilauryl thiodipropionate; 3,3′-Thiodipropionic acid; 3,3′-Thiodipropionic acid, polymer-bound; Didodecyl 3,3′-thiodipropionate; 2,2′-Thiodiacetic acid; 4,4′-Thiodiphenol; Thiodipropionic acid dilauryl ester; 3,3′-Thiodipropanol; Glutathione; 2,2′-(Ethylenedithio)diacetic acid; Ergothioneine; Methionine; 3-Mercaptopropane-1,2-dio; dithionate salts; thioglycolate salts; thiomalate salts; and Lipoyllysine.
 29. The method of claim 15, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are selected from: cysteine and compounds represented by Formula IV:

or a salt, ester, hydrate, solvate, or amide thereof.
 30. The method of claim 15, wherein the one or more compounds having dithio-, thio- or mercapto-containing moieties are selected from N-Acetyl Cysteine, cysteic acid, homocysteic acid, cysteine sulfinic acid, or a salt, ester, hydrate, solvate, or amide thereof.
 31. The method of claim 15, further comprising covering at least a portion of the sensor housing with at least one drug eluting polymer matrix. 